Process for the haloethynylation of gona-ene-3, 17-diones



United States Patent 3,374,255 PROCESS FOR THE HALOETHYNYLATION OFGONA-ENE-SJl-DIONES Thomas B; Windholz, Westfield, and Arthur A.Patchett,

Cranford', NJ., and John Fried, Palo Alto, Calif., assignorsto-Merck &C0,, Inc., Rahway, N.J., a corporation of New-Jersey No Drawing.Continuation-impart. of: application Ser. No. 227,582, Oct. 1,1962..This.- application Apr. 8, 1966, Ser. No. 541,070

6 Claims. (Cl. 260-397.4)

This application is. a continuation-in-part of our copending applicationSer. No. 227,582 filed Oct. 1, 1962, now Patent No. 3,242,197.

This invention is concerned with novel processes for the preparation ofv17a-ethynyland 17ut-haloethynyl-l7t3- hydroxy-gona-4-ene-3 ones whichmay be further unsaturated in the B. and. the C rings. More particularlyit is concerned with the preparation of these valuable compounds, from,the corresponding 3,17-diones without the necessity of protecting the3-keto group.

Amongthe valuable compounds which may be prepared in accordance withthisinvention are those represented by. the formula:

wherein R is hydrogen or methyl; R is hydrogen or lower alkyl; and X ishydrogen, bromine or chlorine. The dotted lines indicate the optionalpresence of double bonds. If a. double bond is present in the9-(10)-position, R is' hydrogen. If a double bond is present in the8(1'4)- position, itrnust be conjugated with double bonds in the 4-andthe 9(-10.)-positions.

Many of the compounds which may be prepared in accordance withthisinvention are physiologically active or can beused to preparephysiologically active compounds which are therapeutically useful fortheir estrogenic, androgenic, progestational orrelated activity. Thecompounds 17u-ethynyl-19-nortestosterone and its 17achloroethynyl analogmay be mentioned by way of example of therapeutically useful compoundswhich may be prepared in accordance with this invention.

Processes are known for the conversion of steroidal 3,17-diones to thecorresponding 17B-hydroxy-17a-ethynyl or haloe'thynyl compounds, but themethods are generallyunsatisfactory, since if the 3-keto group is notprotected, reaction takes place at both the 3- and the 17-p0sitions withthe result that mixtures are obtained which can only be separated withgreat difiiculty. On the other hand, if the 3-keto group is protected,for example by reaction with ethylene glycol, the protecting group mustbe removed in an additional step. This additional step adds to, the costof the preparation and may adversely affect the overall yield.

It is now possible in accordance with this invention to produce thedesired 17a-haloethynyl compounds substantially free, of undesirableby-products without the necessity of protecting the 3-keto group. Thereaction is carried out by reacting the corresponding 3,17-dione with analkali metal chloroacetylide or bromoacetylide in liquid ammonia. Sodiumand potassium are the preferred alkali metals because of their readyavailability. In a further aspect of the invention, the halogen. atom inthe haloethynyl group is selectively removed by a unique reductiveprocedure.

Reaction for the production of Not-ethynyl compounds is mostconveniently etfected'by mixingthe steroid; preferably in a reactioninert organic solvent, especially ether solvents containing up to eightcarbon atoms including cyclic ethers such as dioxane or tetrahydrofuranor dialkyl ethers such as, dimethyl ether, methyl ethyl ether ordi-n-butyl ether, ina liquid ammonia solution containing thehaloacetylide carbanion formedin situ by reaction betweenan alkali metalacetylide. and theselecteddihaloethylene, preferablycis-dichloroethylene; or cis-dibromoethylene. Preferably, the; steroidis added as rapidly as possible so as to minimize side reactions.- Thereaction mixture is held at. the reflux temperature of liquid ammoniafor a period of from about 11/; to about 24 hours to complete thereaction. The preferred; time of reaction which is consistant with highyields under practical operating conditions is from about 2 to 4 hours.

More specifically, reaction may be elf'ected by first forming an. alkalimetal amide by addition ofthe selected alkali metal such: as sodium orpotassium to eX- cess ammonia. From about 0.5 tov about 1.0 mole ofcisdihaloethy-lene per mole of alkali metal is then added to the liquidammonia solution of the alkali metal amide and the mixture allowed. toreflux for from about 15 minutes to -about 2 hours, to form thehaloacetylide. To this mixture there is then added from about 0.5 to 1.0mole of steroid per mole of alkali metal and. the mixture allowed toreact as described above. It is best to addthe steroid at a rate of:from about 1 to 2" grams per minute to obtain the best yields.

The desired product may be isolated in any convenient manner asillustrated -inthe-examples.

For the preparation of the ethynyl compounds in accordance with theprocess of the invention, the haloethynyl compoundis reductivelydehalogenated with-metallic zinc in alower alkanoic acid, which maycontain up to four carbon atoms. Acetic acid is preferred because ofitsready availability.

In the. presently preferred process foreffecting the desired reductivedehalogenation the selected steroid is reacted with from about 0.5 .toabout 2 times its weight of zinc metal based. on the weight of steroidin the selected alkanoic acid. Temperature and time of reaction may varywidely, for example, the reaction-may be carried out duringa, period offrom about one tot-wenty-four hours at a temperature of from about 20 C.to about C. Mostpreferably, from'the' point of view ofobtaining highyields within practical reactiontimes without the necessity of heating,the reaction is carried out at room temperature i.e. 20 C. to 30 C. fromtwo, to four hours. The product normally precipitates and may beseparated by extraction of the. precipitate with an organic solvent,suitably a hydrocarbon or halogenated hydrocarbon solvent containing upto six carbon atoms, preferably chloroform or ethylene dichloride. Theproduct mayv be isolated after; suitable washings and dryings, as.illustrated in the examples, by removal of the solvent at low pressure.

The process of this invention is applicable to a wide variety of3,17-diketosteroids of the gonene series containing 17 to 19 carbonatoms in the steroid nucleus including those which may. have additionalreaction inert substituents such as alkyl groups or halogen atoms. Asspecific examples of compounds which may be prepared by the process: ofthis invention using known 3,1-7,-diketo steroids as starting compoundsthere may be mentioned:

10,13-dimethyl-17a-chloroethynylel'7fl-hydroxyrgona-4- ene-3-one 3l0,13-dimethyl-l7a-bromoethynyl-17p-hydroxy-gona-4- ene-3-one 10,13-dimethyl-17a-ethynyl-17,8-hydroxy-gona-4-ene-3- one13-methyl-17d-chloroethynyl-17B-hydroxy-gona-4-ene-3- one13-metl1yl-17u-bromoethynyl-17B-hydroxy-gona-4-ene- 3-one13-rnethyl-17a-ethynyl-17fi-hydroxy-gona-4-ene-3-one 13-methyl-17a-chloroethynyl- 17B-hydroxy-gona-4,9

diene-3-one 13-methyl-17a-bromoethynyl-17/3-hydroxy-gona-4,9( 10)diene-3-one Other starting materials useful in accordance with theprocess of this invention may be prepared in accordance with theprocedures illustrated in the following preparations.

PREPARATION 1 The following illustrates the preparation of 6-oxo-1-vinyl-2,3,4,6,7,8-hexahydronaphthalene, which may also be designated as1-vinyl-A -hexalone-6, starting from 6-methoxy-a-tetralone.

Step 1.-Preparati0n of 1,2,3,4-tetrahydro-6-methoxy- I-naphthol OII(fi-methoxy-a-tetralone) (1, 2 3, 4-tetrahydro-6- methoxy-l-naphthol)Eight grams of 6-methoxy-a-tetralone, the synthesis of which has beenreported by G. Stork in JACS, 69, 576

(1947), are dissolved in 320 m1. of methanol and cooled to 0 C. Afreshly prepared'solution of 8 g. NaBI-L; in 80 ml. H O is added withstirring. The resulting solution is stirred for an additional 12 hoursat room temperature, neutralized with NaH PO and the methanol removed invacuo. The residue is extracted with ether, washed with water, dried andconcentrated to a heavy oil; yield 7.10 grams of1,2,3,4-tetrahydro-6-methoxy-1- naphthol. The reaction of Step 1 may berepresented by the above equation.

Step 2.Preparation of 6-ox0-1-vinyl-2,3,4,6,7,8-

hexahydronaphthalene The 1,2,3,4-tetrahydro-6-methoxyl-naphthol obtainedfrom Step 1 is converted to6-oxo-l-vinyl-2,3,4,6,7,8-hexahydronaphthalene substantially accordingto the process described in IZvest. Akad. Nauk SSSROtdel. Khim. Nauk,1803 (1961). The conversion involves four steps which may be representedin fiow chart form as follows:

(IV) (V) (i) REDUCTION OF 1,2,3,4,-TET RAHYDRO-6-METHOXY-1- NAPHTHOL6.65 grams of 1,2,3,4-tetrahydro-6-methoxy-l-naphthol (I), the reductionproduct obtained in Step 1, are dissolved in a mixture of 160 ml.tctrahydrofuran and 160 4 ml. tertiary-butanol, which is then added to around bottom flask fitted with a reflux condenser and containing 10.3 g.sodium in 390 ml. liquid ammonia. The system is purged with nitrogen gasand the mixture refluxed for 4 /2 hours. The flask is then cooled, 25m1. methanol are added and the ammonia is evaporated off. The residue isconcentrated in vacuo and the 1,2,3,4,5,8-hexahydro-6- methoxyA -hexalolis extracted by the conventional ether-water distribution technique. Theether layer is separated and the aqueous layer is further extracted withether. The combined ether extracts are washed with water, dried overanhydrous K CO and concentrated in vacuo to yield 6.40 grams of (II).

(ii) OXIDATION OF 1,2,3,4,5,S-HEXAHYDRO-G-METHOXY- l-NAPH'IHOL 12 gramsof aluminum isopropoxide and 6.40 grams of (II) are added to 28 ml. ofdry toluene under nitrogen and dissolved therein with slight heat. 16m1. dry acetone are added and the mixture refluxed for 4 /2 hours. Themixture is then cooled, 12 ml. of water are added and the mixture isextracted four times wtih ether. The ether extracts are combined, driedover anhydrous K CO and concentrated in vacuo to yield 6.00 g. of3,4,5,8-tetrahydro-a-tetralone.

(iii) PREPARATION OF VINYLCARBINOL A freshly prepared solution of 16 g.of vinyl bromide in 16 ml. tetrahydrofuran is added to 2.54 gramsmagnesium in 22 ml. tetrahydrofuran under a nitrogen atmosphere toprepare vinylmagnesium bromide (Grignard reagent). To this is added 5grams of (III), dissolved in a mixture of 22 ml. ether and 6.3 ml.tetrahydrofuran. After 24 hours, the mixture is boiled for 1 /2 hours,cooled and poured into a mixture of 15 g. of ammonium chloride and g. ofice. The organic layer is separated and the aqueous layer is extractedthree times with ether. The extracted1,2,3,4,5,8-hexahydro-6-methoxy-l-vinyl-lnaphthol (IV) need not beisolated before proceeding with the next step.

(iv) PREPARATION OF TRIENEONE The ether extracts of Step 2 (iii) areadded to a mixture of ml. of 2.5 N NCl and 20 g. of ice and stirred for4 hours at room temperature under nitrogen. The ether layer is separatedand the aqueous layer extracted with ether. The combined ether extractsare washed two times with aqueous NaHCO two times with ice cold water,dried over Na SO and concentrated in vacuo to yield 4.10 g. of6,0xo-1-vinyl-2,3,4,6,7,8-hexahydronaphthalene (V), a yellow oil.

PREPARATION 2 I Me 108 grams (2 moles) of fresh sodium methoxide arecarefully dissolved in ice-cooled 580 ml. absolute alcohol and thencooled to 5 C. With stirring and continued cooling, a mixture of 72 g.(1 mole) of ethylmethylketone and 320 g. (2.2 moles) of diethyloxalateis added over a period of 30 minutes and then heated at 50 C. for 40minutes. The mixture is cooled in an ice bath and, with strong stirring,a cold mixture of 55 m1. conc. H 50 and 55 ml. H O is slowly added.After addition, the reaction mixture is allowed to come to roomtemperature and the salt filtered. The filtrate is concentrated in vacuoto about 200 ml. On cooling, a precipitate is obtained, which isrecrystallized from ethyl acetate. The resulting crystalline product,4-methyl-2,3,5-trioxycyclopentane glyoxylic acid ethyl ester, isfiltered and dried; yield: 70 g.; M.P. 158160 C. The reaction of Step 1may be represented by the above equation.

Step 2.-Preparati0n 0f diketosemicarbazone 70 grams (0.31 mole) of thetriketoglyoxalate obtained from Step 1 is suspended in 1050 ml. of 2.5 NHCl and slowly heated with stirring to reflux. After refluxing for about1 hour, the solution is cooled to room temperature and added to an equalvolume of alcohol. At room temperature there is then added dropwise withstirring over a period of 1 /2 hours a solution of 53.5 g. (0.79 mole)of semicarbazide-HCI and 74 g. of Nat-acetate in 490 ml. H O. Aprecipitate of 3-methyl-2,4-cyclopentadione-lsemicarbazone is obtained;yield: 54 g. The material has no sharp melting point, decomposing around290 C. The reaction of Step 2 may be represented by the above equation.

Fifty-four grams of KOH are dissolved with stirring in 540 ml. ethyleneglycol and the solution heated to 130 C. Fifty-four grams of thesemicarbazone obtained in Step 2 is then added gradually and Withstirring and the mixture refluxed for 1 /2 hours. The mixture is thencooled and concentrated under vacuum (0.5 mm.) to drymess. The residueis dissolved in water, ice-cooled and acidified to pH 3. A precipitateof Z-methylcyclopentane- 1,3-dione is obtained which is filtered off anddried; yield: 27.4 g.; M.P.: 205-208 C. The reaction of Step 3 may berepresented by the above equation.

PREPARATION 3 The procedures of Preparation 2 are followed except thatequivalent quantities of other ketones are utilized in place of theethylmethyl ketone of Step 1 therein, thereby obtaining variousderivatives of cyclopentane-1,3-dione. Accordingly, the use of otherlower alkylmethyl ketones, such as propylmethyl ketone, isobutylmethylketone, nbutylmethyl ketone and amylmethyl ketone, yields thecorresponding 2-lower alkylcyclopentane-l,3-dione compounds, such as2-ethylcyclopentane-1,3-dione, Z-isopropylcyclopentane-1,3-dione,2-n-propylcyclopentane-1,3-dione and Z-n-butylcyclopentane-1,3-dione,respectively.

6 PREPARATION 4 This preparation illustrates the preparation of 13-methyl gona 4,8(14), 9 triene-3,l7-dione from the interaction of 6 oxo2,3,4,6,7,8 hexahydronaphthalene and 2 methylcyclopentane-1,3-dione, Thereaction may be represented as follows:

6.50 grams of 6 0x0 1-vinyl-2,3,4,6,7,8-hexahydro naphthalene aredissolved in a mixture of dry xylene (27 ml.) and tertiary-butanol (13.5ml.) and to this are added 4.05 g. of Z-methylcyclopentane-1,3-dione and1.81 ml. diethylamine. The resulting mixture is refluxed for 40 hoursand then concentrated in vacuo. The residue is dissolved in methylenechloride, washed successively with aqueous NaHCO dilute HCl and water,dried and concentrated in vacuo. The resulting concentrate ischromatographed on acid washed alumina and eluted withbenzene-chloroform mixtures to yield 1.6 g. of 13-methylgona 4,8(14),9triene-3,17-dione, M.P. -131" C. Analysis of the product found C=80.90%,H=80.56%, H=7.51% UV. absorption data revealed; A max.=3500; e=24,200.

PREPARATION 5 Using the same procedure as in Preparation 4,6-oxo-1-vinyl 2,3,4,6,7,8-hexahydronaphthalene is reacted with thecyclopentane-l,3-dione derivatives listed in Table I to yield thecorresponding gona 4,8(14),9-triene-3,17- dione compounds.

TABLE I Cyclopentane-1,3-dione derivative:

Z-ethyl-cyclopentane-1,3-dione 2-isopropyl-cyclopentane-1,3-dio-ne2-n-propyl-cyclopentane-1,3-dione Z-n-butyl-cyclopentane-1,3-dioneCorresponding gona-4,8(14) ,9-triene-3,17 dione:

13-ethyl-gona-4,8( 14) ,9-triene-3,17-dione 13 -isopropyl-gona-4,8( 14),9-triene-3 ,17-dione l3-n-propy1-gona-4,8(14),9-triene-3,17-dione 1 3-n-butyl-gona-4,8 14) ,9-triene-3 ,17-dione In accordance with the aboveprocedures, gona-4,8 (14),9-triene-3,17-dione is prepared from theinteraction of 6 oxo-1-vinyl-2,3,4,6,7,8-hexahydronaphthalene andcyclopentane-1,3 -dione.

This preparation illustrates the preparation of l3-Rgona-4,8(14),9-triene-3,17-dione wherein R is a hydrogen atom or a loweralkyl radical.

The following non-limiting examples are given by way of illustrationonly.

Example This example illustrates the preparation of 13-methyl- 17achloroethynyl 17-hydroxy-gona-4,8(14),9-triene-3- one. The reaction maybe represented as follows:

0 OH Me I Me oEo-o1 A solution of 0.144 ml. cis-dichloroethylene in 0.45ml. dry other is added to a solution of sodamide in 4.5 ml.

liquid ammonia (prepared from 105 mg. sodium), thereby forming thechloroacetylide carbanion in situ, and the resulting mixture is refluxed(circa --30 C.) for 30 minutes. To this is added a solution of 300 mg.of the 13- methyl gona-4,8(14),9-triene-3,17-dione obtained fromPreparation 4 in 3 ml. dry tetrahydrofuran and refluxing (circa 30 C.)is continued for 1 hours. After cooling to room temperature, the productis poured onto a mixture of NH Cl and ice, extracted with ether and theether extract washed with dilute HCl, aqueous NaHCO water and thendried. The extract is then chromatographed on acid Washed alumina andeluted with benzene-chloroform mixtures to yield 150 mg. of 13- methyl17oz -chloroethynyl-17-hydroxy-gona-4,8(14),9- triene-3-one, M.P.:159-160 C. Analysis of the product found C=72.97%, H=6.45%; calculatedC:72.98%, H=6.39%. UV. absorption data revealed: x max.=3 57 5,e=19,850.

The corresponding 17a-bromoethynyl compound is similarly prepared byreplacing the cholorethylene with an equivalent quantity ofcis-dibromoethylene.

Example 2 Using the same procedure as in Example 1, cis-dichloroethyleneor cis-dibromoethylene is reacted with the 13 alkylgona-4,8(l4),9-triene-3,17-dione compounds listed in Table I ofPreparation 5 to yield, respectively, the corresponding 13 alkyl 17ahaloethynyl-17fi-hydroxy gona 4,8(l4),9-triene-3-one compounds tabulatedin Table II.

TABLE II 13-ethyl-17a-chloroethynyl-17B-hydroxy-gona- 4,8( 14),9-triene-3-one 13-isopropyl-17a-chloroethynyl-17B-hydroxy-gona-4,8(l4),9-triene-3-one 13-n-propyl-17a-chloroethynyl-17,9-hydroxy-gona-4,8 l4) ,9-triene-3-one 13-n-butyl-17a-chloroethynyl-l7fl-hydroxy-gona-4,8 14) ,9-triene-3-one 13-etl1yl-l7a-bromoethynyl-17B-hydroxy-gona- 4,814) ,9-t1'iene-3-one 13-isopropyl-17ot-bromoethynyl-l7fi-hydroxy-gona-4,8 l4) ,9-triene-3-one 13-n-propy1-17a-bromoethynyl-17/3-hydroXy-gona4,8(14) ,9-triene-3-one 13-n-butyl-17a-bromoethynyl-l7p-hyd roxy-gona-4,8(14),9-triene-3-one 13 -methyl- 17a-bromoethynyl- 17 ,9-hydroxy-gona- 4,8 l4) ,9-triene-3-one Example 3 To 76 ml. of dry distilled liquidammonia is added in portions 1.455 g. of sodium metal. After each of thefirst 34 portions, one crystal of ferric nitrate is added and themixture stirred until the blue color disappears and the gray sodamideprecipitates. The balance of the sodium is added portion-wise withoutthe use of ferric nitrate.

After completion of the preparation of the sodamide, 2.1 ml. ofcis-dichloroethylene in 6.6 ml. of dry ether is added dropwise with DryIce cooling. The cooling is discontinued and the reaction mixtureallowed to refiux for 30 minutes.

To this mixture is added 6.5 g. of l3-methyl-gona-4- ene-3,17-dione in65 ml. of dry tetrahydrofuran in portions over a period of minutes. Thethick reaction mixture is stirred well for 4 hours. At the end of thisperiod, excess ammonium chloride is added to destroy excess sodium.Approximately 100 ml. of ether is added and the ammonia allowed toevaporate. The reaction mixture is then poured into an ice-watermixture, the ether phase separated and the aqueous phase extracted withether. The combined ether extracts are dried, filtered and the solventremoved under low pressure. The product, 13- methyl 17o: chloroethynyl17,8 hydroxy gona 4- ene-3-one may be purified by recrystallization orchromatographically.

This procedure is utilized to prepare the following compounds utilizingthe appropriate steroid starting material; and, where necessaryreplacing the dichloroethylene with an equivalent quantity ofcis-dibromoethylene. With the last five compounds, an equivalentquantity of potassium is employed in place of the sodium.

13-rnethyl-17a-bromocthynyl-17,8-hydroxy-gona-4-ene- 3 one13-ethyl-17a-bromoethynyl-17fl-hydroxy-gona-4-ene-3- one 13-n-propyl-17a-bromoethynyl- 1 7fi-hydroxy-gona-4-ene- 3-one 13-isopropyl-17a-bromoethynyl-17fi-hydroxy-gona-4- ene-3-one13-n-butyl-17a-bromoethynyl-17fi-hydroxy-gona-4-ene-13-ethyl-17a-chloroethynyl-17B-hydroxy-gona-4-ene-3- one13-n-propyl-17a-chloroethynyl-17/3-hydroxy-g0na-4-ene- 3-one 13-n-isopropyl-17a-chloroethynyl-17{3-hydroxy-gona-4- ene-3-one13-n-butyl-17a-chloroethynyl-17/3-hydroxy-gona-4-ene- 3-one13-methyl-17a-chloroethynyl-l 7;8-hydroxy-gona-4,9

( 10 -dione-3-one 13-ethyl-17a-chloroethynyl-17/8-hydroxy-gona-4,9( 10)dione-3 -one 13-n-propyl-17a-ch1oroethynyl-17fl-hydroxy-gona-4,9

(10 -dione-3 -0ne 13-isopropyl- 17 a-chloroethynyl- 17,B-hydroxy-gona-4,9

( 10 -dione-3 -one 13-n-butyl-17a-chloroethynyl-17B-hydroxy-gona-4,9

(10) -dione-3-one 13 -methyl-17a-bromoethynyl-l7B-hydroxy-gona-4,9 10)dione-3-one 13-ethyll7a-bromoethynyl-17/3-hydroxy-gona-4,9 1O

dione-3 -0ne 13-isopropyl-17a-bromoethynyl-17fl-hydroxy-gona-4,9

(10 -dione-3 -0ne 13-n-butyl-17a-bromoethynyl-17/8-hydroxy-gona-4,9

( 10 -dione-3-one Example 4 A total of 2.5 g. of13-methyl-17a-chloroethynyl-17phydroxy-gona-4-ene-3-one is taken up inml. of glacial acetic acid and 2.5 g. of zinc powder is added over aperiod of one hour at room temperature with good stirring. Stirring iscontinued for an additional 4 hours. The precipitate is filtered, washedwith chloroform and the combined filtrates diluted with chloroform andwashed successively with water, three times with dilute aqueous sodiumbicarbonate and again with water. The chloroform solution is dried,filtered and concentrated under low pressure to precipitate13-methyl-17a-ethynyl-17fihydroxy-gona-4-ene-3-one which may be purifiedby crystallization.

This procedure is followed for the reduction of the l7a-chloroethynyland 17a-bromoethynyl compounds prepared as described above to preparethe following compounds:

13 -ethyl-17a-ethynyl-17B-hydr0xy-gona-4-ene-3 -one13-n-propyl-17a-ethynyl-17,8-hydroxy-gona-4-ene-3-one13-isopropyl-17a-ethynyl-175-hydroxy-gona-4-ene-3-one13-n-butyl-17a-ethynyl-17flhydroxy-gona-4-ene-3 -one 13-methyl-17a-ethynyl- 1 7fi-hydroxy-gona-4,9 10 -dione- 3-onel3-ethyl-17a-ethynyl-l7fl-hydroxy-gona-4,9(10)-dione- 3 -one13-n-propyl- 17a-ethynyl- 1 7fl-hydroxy-gona-4,9 10

dione-3-one Examples 5-7 The following table summarizes the proceduresof specific examples for the preparation of13-rnethyl17achloroethynyl-17/3-hydroXy-gona-4-ene-3-one. All reactionsare carried out in liquid ammonia.

TABLE III Moles of Reflux Ex. Solvent Moles of Period,

Steroid Dichloro- Sodium hrs.

ethylene 5 0. 5 0. 5 THF 0. 5 24 6 1. 1. 0 Dioxane 1. 0 1. 7 0.5 1. 0n-Butyl ether... 1.0 4

Examples 8-1] The following table summarizes the procedures of specificexamples for the preparation of13-11'l6thYl-17aethynyl-l7fl-hydroxy-gona-4-ene-3-one form thecorresponding chloroethynyl compound (Examples 8 and 9) and bromoethynylcompound (Examples 10 and 11).

TABLE IV Grams of- 'lernp., Reaction Example 0. Acid Period,

Steroid Zinc hrs,

What is claimed is: 1. A process for the haloethynylation of gona-4-ene-10 3,17-diones and B- and O ring unsaturated derivatives thereof inwhich the double bonds are conjugated with the double bond at the4-position, and in which the keto groups at C3 and C-17 are both in freeunprotected form, to produce the corresponding 17a-haloethynyl-17;8-hydroxy-gona-4-ene-3-ones which comprises reacting the said 3,17-dioneswith a dihaloethylene in liquid ammonia in the presence of an alkalimetal amide, said dihaloethylene being selected from the groupconsisting of dichloroethylene and dibromoethylene.

2. A process as in claim 1 wherein the dihaloethylene iscis-dichloroethylene and the compound produced is a 17a-chloroethynylcompound.

3. A process as in claim 1 wherein the starting gona-4- ene is13-mcthyl-gona-14,8( l4),9-triene-3,l7-dione, the dihaloethylene is cisdichloroethylene and the compound produced is13-methyl-17a-chloroethynyl 17,8 hydroxygona-4,8 l4) ,9-triene-3-one.

4. A process as in claim 1 wherein the starting gona- 4-ene is13-methyl-gona-4-ene-3,17-dione, the dihaloethylene iscis-dichloroethylene and the compound produced is13methyl-17a-chloroethynyl-17,8-hydroxy-gona- 4-ene-3-one.

5. A process as in claim 1 wherein the starting gona-4- ene is13-methyl-gona-4,9-diene-3-one, the dihaloethylene iscis-dichloroethylene and the compound produced is 13- methyl-17a-chloroethynyb17B-hydroXy-gona 4,9 diene- 3-one.

6. A process as in claim 1 wherein the starting gona- 4-ene is10,13-dimethyl-gona-4-ene-3-one, the dihaloethylene iscis-dichloroethylene and the compound produced isl3-methyl-l7rx-chloroethynyl-17/3-hydroxy-gona 4 ene- 3-one.

References Cited ELBERT L. ROBERTS, Primary Examiner.

1. A PROCESS FOR THE HALOETHYNYLATION OF GONA-4-ENE3,17-DIONES AND B-AND C- RING UNSATURATED DERIVATIVES THEREOF IN WHICH THE DOUBLE BONDSARE CONJUGATED WITH THE DOUBLE BOND AT THE 4-POSITION, AND IN WHICH THEKETO GROPS AT C-3 AND C-17 ARE BOTH IN FREE UNPROTECTED FORM, TO PRODUCETHE CORRESPONDING 17A-HALOETHYNYL-17BHYDROXY-GONA-4-ENE-3-ONES WHICHCOMPRISES REACTING THE SAID 3,17-DIONES WITH A DIHALOETHYLENE IN LIQUIDAMMONIA IN THE PRESENCE OF AN ALKALI METAL AMIDE, SAID DIHALOETHYLENEBEING SELECTED FROM THE GROUP CONSISTING OF DICHLOROETHYLENE ANDDIBROMOETHYLEN.